The long range goal of this project is to understand the processes involved in cerebral ischemia and stroke and how to non-invasively quantitate some of these processes by magnetic resonance imaging (MRI) and use MRI to predict the outcome of cerebral ischemia in humans. This information could also guide the treatment of stroke patients and improve their neurological outcome. A highly reproducible, readily reversible rat model of unilateral middle cerebral artery (MCA) occlusion (0, 40, and 120 minutes and permanent occlusion) will be used. The five MRI parameters to be measured are proton spin density (p), spin-lattice and spin-spin relaxation times (T1 and T2, respectively), the "apparent" diffusion coefficient of water (ADCw) and cerebral blood flow (MRI-CBF). For Specific Aim 1, cerebral blood flow (CBF) will be virtually simultaneously measured in rat brain with 14C-iodoantipyrine quantitative autoradiography (OAR-LCBF) and with MRI-CBF at various times after occluding the MCA. These data will be used to test the hypothesis that flow continually changes within and around ischemic brain tissue during the periods of occlusion and reperfusion and that the changes detected by MRI are parallel with but not identical to those determined by QAR-LCBF, which are the more reliable. For Specific Aim 2a, histological indices (neuronal density and viability and volume of damage) and MRI measures of the state of water in brain tissue and MRI-CBF will be concurrently quantitated at specific times after either permanent or transient MCA occlusion. These results will be used to test athe hypothesis that neuronal alterations and tissue damage in ischemic brain at one or more times will be accurately reflected by some combination of MRI measures of the state of water and/or MRI-CBF. For Specific Aim 2b, the temporal relationship between CBF and ADCw following permanent or transient MCA occlusion will be investigated with some of the data from the preceding experiments. The hypothesis that will be tested with this analysis is that ADCw in brain tissue, shortly after the onset of ischemia is coupled to the changes in CBF but at later times becomes relatively independent of flow. Finally, for Specific Aim 3, the volume of brain infarction will be measured from a set of histological sections taken at 7 days post-ischemia and used to identify a set of MRI parameter derived estimates of infarct volume that predict the histologically determined volume of infarct These data will be used to test the hypothesis that the severity of histologically indicated injury 7 days after MCA occlusion can be predicted by some combination of MRI parameters and time(s) of measurement. The significance of this research is the potential to develop clinically relevant, noninvasive methods for identifying the stage, severity, treatment, and neurologic outcome of stroke-induced brain injury in humans.